Aims/hypothesis Chronic sub-acute inflammation contributes to the pathogenesis of type 2 diabetes mellitus and cardiovascular disease. High doses of salicylate reduce inflammation, glucose and triacylglycerols, and may improve insulin sensitivity, suggesting therapeutic potential in impaired fasting glucose and/or impaired glucose tolerance. This trial aimed to evaluate the effect of salsalate vs placebo on insulin resistance and glycaemia in impaired fasting glucose and/or impaired glucose tolerance. Methods We conducted a 12 week, two-centre, randomised, placebo-controlled study to evaluate the effect of salsalate (up to 4 g/day) vs placebo on systemic glucose disposal. Secondary objectives included treatment effects on glycaemia, inflammation and cardiovascular risk factors. Seventy-eight participants with impaired fasting glucose and/or impaired glucose tolerance from two VA healthcare systems were enrolled. Randomisation assignment was provided by the coordinating center directly to site pharmacists, and participants and research staff were blinded to treatment assignment. Results Seventy-one individuals were randomised to placebo (n = 36) or salsalate (n = 35). Glucose disposal did not change in either group (salsalate 1% [95% CI −39%, 56%]; placebo 6% [95% CI −20%, 61%], p = 0.3 for placebo vs salsalate). Fasting glucose was reduced by 6% during the study by salsalate (p = 0.006) but did not change with placebo. Declines in glucose were accompanied by declines in fasting C-peptide with salsalate. Insulin clearance was reduced with salsalate. In the salsalate group, triacylglycerol levels were lower by 25% (p = 0.01) and adiponectin increased by 53% (p = 0.02) at the end of the study. Blood pressure, endothelial function and other inflammation markers did not differ between groups. Adipose tissue nuclear factor κB (NF-κB) activity declined in the salsalate group compared with placebo (−16% vs 42%, p = 0.005), but was not correlated with metabolic improvements. The frequency of tinnitus was low but tended to be higher with salsalate therapy (n =4 vs n =2). Conclusions/interpretation In summary, salsalate therapy was well tolerated, lowered fasting glucose, increased adiponectin and reduced adipose tissue NF-κB activity. These changes were not related to changes in peripheral insulin sensitivity, suggesting additional mechanisms for metabolic improvement. Trial registration ClinicalTrials.gov NCT00330733 Funding Office of Research and Development, Medical Research Service, Department of Veterans Affairs and NIH K24 DK63214
We have used an immunoradiometric assay for intact PTH in conjunction with calcium and citrate infusions to study whether levels of intact PTH are responsive to reversal of the direction of change in ionized calcium in normal humans. Eleven normal subjects received graded infusions of citrate or calcium on separate days to produce linear rates of decrease or increase in calcium. After discontinuation of the infusions, the return of calcium toward baseline was followed. Six subjects were given an infusion of citrate after the calcium infusion to speed the recovery of calcium toward baseline. Citrate-induced hypocalcemia produced a rise in serum PTH levels from 28.1 +/- 3.6 to 69.4 +/- 4.8 ng/L as calcium fell from 1.26 +/- 0.01 to 1.06 +/- 0.02 mmol/L. As calcium returned toward baseline, PTH levels fell dramatically, reaching levels indistinguishable from baseline despite persistent hypocalcemia. Slopes of regression lines defining the PTH-calcium relationships during decreasing and increasing calcium levels were significantly different. Those subjects receiving a calcium infusion alone showed a prompt suppression of PTH levels. As calcium returned toward baseline after the infusion, a modest decline in calcium produced no significant change in the PTH-calcium relationship. When citrate was used to return calcium to baseline, PTH levels rose from 7.8 +/- 2.0 to 55.0 +/- 6.8 ng/L as calcium fell from 1.42 +/- 0.02 to 1.26 +/- 0.02 mmol/L and defined a regression relationship significantly different from the period of increasing calcium. Thus, a hysteretic relationship between ionized calcium and levels of intact PTH can be induced in normal humans by reversing the direction of change in calcium. Therefore, the role played by calcium concentration per se in controlling PTH secretion may be part of more complex and dynamic regulatory mechanisms.
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